The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes.
The enhancement of activity rescues the establishment of Mecp2 null neuronal phenotypes.
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DOI：
10.15252/emmm.202012433
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发表时间：
2021-04-09
影响因子：
11.1
通讯作者：
Landsberger N
中科院分区：
文献类型：
--
作者：
Scaramuzza L;De Rocco G;Desiato G;Cobolli Gigli C;Chiacchiaretta M;Mirabella F;Pozzi D;De Simone M;Conforti P;Pagani M;Benfenati F;Cesca F;Bedogni F;Landsberger N
MECP2突变导致Rett综合征（RTT），这是一种严重的进行性神经发育障碍，主要影响女性。虽然RTT患者表现出延迟发作的症状，但一些证据表明，MeCP2缺乏会改变大脑的早期发育。事实上，在早期成熟过程中，Mecp2空皮质神经元显示广泛的转录变化，活性降低，和有缺陷的形态。有人提出，在大脑发育过程中，这些元素在前馈循环中相互联系，神经元活动驱动转录和形态变化，进一步提高网络成熟度。我们假设，在早期成熟过程中神经元活性的增强可能会阻止RTT典型分子和细胞表型的发生。因此，我们表明，通过向神经元培养物中加入安帕金CX 546获得的兴奋性的增强拯救了几个基因的转录、神经元形态和对刺激的反应。早期治疗效果更好。在体内，短时间和早期给予Mecp2缺失小鼠CX 546延长寿命，延迟疾病进展，并挽救运动能力和空间记忆，从而证实了RTT早期恢复神经元活性的价值。神经元活动驱动转录和形态变化，确保成熟。这种机制受到Mecp2缺失的影响。我们展示了通过增强Mecp 2空神经元活性产生的拯救作用，并提出了治疗Rett综合征的新治疗时间窗。
MECP2 mutations cause Rett syndrome (RTT), a severe and progressive neurodevelopmental disorder mainly affecting females. Although RTT patients exhibit delayed onset of symptoms, several evidences demonstrate that MeCP2 deficiency alters early development of the brain. Indeed, during early maturation, Mecp2 null cortical neurons display widespread transcriptional changes, reduced activity, and defective morphology. It has been proposed that during brain development these elements are linked in a feed‐forward cycle where neuronal activity drives transcriptional and morphological changes that further increase network maturity. We hypothesized that the enhancement of neuronal activity during early maturation might prevent the onset of RTT‐typical molecular and cellular phenotypes. Accordingly, we show that the enhancement of excitability, obtained by adding to neuronal cultures Ampakine CX546, rescues transcription of several genes, neuronal morphology, and responsiveness to stimuli. Greater effects are achieved in response to earlier treatments. In vivo, short and early administration of CX546 to Mecp2 null mice prolongs lifespan, delays the disease progression, and rescues motor abilities and spatial memory, thus confirming the value for RTT of an early restoration of neuronal activity. Neuronal activity drives transcriptional and morphological changes that ensure maturation. Such mechanism is affected by Mecp2 absence. We show the rescue effects produced by enhancing Mecp2 null neurons activity and propose new therapeutic time windows for the treatment of Rett syndrome.
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影响因子：
14.5
作者：
Banerjee, Abhishek;Miller, Meghan T.;Kaufmann, Walter E.
通讯作者：
Kaufmann, Walter E.
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通讯作者：
Tongiorgi, Enrico
影响因子：
3.8
作者：
de Groot, Martje W. G. D. M.;Dingemans, Milou M. L.;Westerink, Remco H. S.
通讯作者：
Westerink, Remco H. S.